5-Hydroxytryptamine (5-HT), also called as serotonin, is either an important monoamine neurotransmitter, or a vasoactive substance, 5-HT is widely distributed in central nervous system (CNS), participates the control and regulation of almost all physiological and behavior functions in human body, including feelings, cognitions, sensations, neurotrophy, appetite, endocrine function, gastrointestinal tract function, motion function, sex behavior and sleep. The studying of various 5-HT receptors (5-HTR) facilitates the interpretation of various physiological and pathological mechanisms of nerve and mental disorders, as well as the formulation of corresponding therapeutic strategy. At present, human 5-HTR has at least 7 types (5-HT1R to 5-HT7R), these 7 kinds of receptors can be further divided into several subtypes. Among numerous subtypes of 5-HTR, the research of 5-HT1AR is the deepest and widest one, and the development of prospect of ligands thereof is very promising.
5-HT1AR is an important regulation factor for 5-HT system neural transmission. When neural impulse reaches nerve terminal, presynaptic membrane vesicles release neurotransmitter 5-HT to synaptic cleft. After acting with 5-HTR of synaptic membrane, most of the 5-HT is subjected to selective serotonin reuptake (SSR) and enters back into presynaptic membrane, in which a part thereof enters again into synaptic vesicles for storage, another part is degraded by monoamine oxidase to terminate activity thereof 5-HT1AR signal transductions are all performed by coupling to G protein, inhibiting adenylate cyclase activity, therefor decreasing the synthesis of second messenger cyclic adenosine monophosphate (cAMP), activating potassium ion channels, resulting hyperpolarization of membrane, forming inhibitory post synaptic potential, and then initiating cytological effects.
In addition, 5-HT1AR further participates the regulation of hypothalamic-pituitary-adrenal axis (HPA) which has important functions in stress response. Many researches confirm that 5-HT1AR plays very important role in many functional activity of central nervous system, and closely relates to anxiety, depression, schizophrenia, pain, cognition, eating behavior, sex activity, Alzheimer disorder and sleep-waking cycle, etc.
Hence, it has important significance to develop a novel selective regulation ligand of 5-HT1AR (5-HT1ARL), for example, the well-known 5-HT1AR partial agonists (e.g., buspirone, etc.) are important anxiolytic drug widely used in clinic, meanwhile, they also have antidepressant activity.
Selective serotonin reuptake inhibitors (SSRIs) selectively target on 5-HT transporter, they are current first-line antidepressants and anxiolytics in clinic, such as sertraline, fluoxetine and paroxetine, etc.
Many experimental and clinical data show that the use of combination of 5-HT1ARL drug and selective serotonin reuptake inhibitor (SSRIs) drug can shorten onset time, and enhance the therapeutic efficiency. The design and synthesis of novel ligands having dual activities of 5-HT1ARL and SSRI, and proceeding related pharmacological study thereof will very helpful in the development of novel, fewer side-effects and faster onset neuropsychoactive drugs including antidepressants, anxiolytics and cognition enhancer ect.
The early data found that aryl piperazine compound Vilazodone (EMD 68843) is a dual 5-HT1AR partial agonist and SSRIs, which exhibits well antidepressant effect, and is in phase III clinical research, but its clinical therapeutic effects are still not satisfied (M E Page, et al. J Pharmacol Exp Ther, 2002, 302: 1220; M J Milan. Neurotherapeutics, 2009, 6: 53). SB-649915 has 5-HT1A/1BR antagonistic effect and inhibit 5-HT reuptake, and it exert faster anxiolytic effects (M J Milan. Neurotherapeutics, 2009, 6: 53). At present, it is mainly based on the dual 5-HTRL and SSRI action mechanism to attempt to incorporate the pharmacophores of the both into one molecule, for example, a substituted indole ring or benzothiophene ring having activity to 5-HT transporter can be organically linked to a pharmacophore (e.g., arylpiperazine or tetrahydroisoquinolin) having function to 5-HT1AR, to achieve dual functions of using the same one small molecule to regulate 5-HT1AR and inhibit 5-HT transporter at the same time, so as to bring about effects of quick onset in anti-depression and antianxiety (L I Peng, YANG Rifang, L I Jin, YUN Liuhong. Advances in research of 5-hydroxytryptamine (5-HT)1A receptor ligand. Chinese Journal of Medicinal Chemistry, 2008, 18(3), 228-238).
At present, it is still in need to find novel compounds having dual activities to 5-HT1ARL and SSRI for clinical application.